RAG1 splicing mutation causes enhanced B cell differentiation and autoantibody production.
RAG1 splicing mutation causes enhanced B cell differentiation and autoantibody production.
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RAG1剪接突变导致B细胞分化和自身抗体产生增强
DOI：
10.1172/jci.insight.148887
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发表时间：
2021-10-08
期刊：
影响因子：
8
通讯作者：
Wang JY
中科院分区：
文献类型：
--
作者：
Min Q;Meng X;Zhou Q;Wang Y;Li Y;Lai N;Xiong E;Wang W;Yasuda S;Yu M;Zhang H;Sun J;Wang X;Wang JY
亚型RAG 1或RAG 2突变引起原发性免疫缺陷，并可导致自身免疫，但其潜在机制尚不清楚。我们在此报告一例RAG 1第一内含子中携带c.116+ 2 T>G纯合剪接位点突变的患者，该突变导致异常剪接并大大降低RAG 1蛋白表达。B细胞发育在前B细胞向前B细胞转变和前B细胞向未成熟B细胞分化步骤中均被阻断。患者B细胞具有减少的B细胞受体库多样性和减少的互补决定区3长度。尽管存在B细胞淋巴细胞减少症，但患者BM中有大量浆细胞，并产生大量IgM和IgG抗体，包括自身抗体。幼稚B细胞的比例降低，而IgD-CD 27-双阴性（DN）B细胞的频率大大增加，所述细胞在刺激后迅速分化成Ab分泌浆细胞。对52例原发性免疫缺陷患者的免疫表型分析显示DN B和记忆B细胞比例增加与幼稚B细胞数量和比例减少密切相关。这些结果表明，淋巴细胞减少的环境触发幼稚B细胞分化为DN B和记忆B细胞，导致Ab产生增加。
Hypomorphic RAG1 or RAG2 mutations cause primary immunodeficiencies and can lead to autoimmunity, but the underlying mechanisms are elusive. We report here a patient carrying a c.116+2T>G homozygous splice site mutation in the first intron of RAG1, which led to aberrant splicing and greatly reduced RAG1 protein expression. B cell development was blocked at both the pro-B to pre-B transition and the pre-B to immature B cell differentiation step. The patient B cells had reduced B cell receptor repertoire diversity and decreased complementarity determining region 3 lengths. Despite B cell lymphopenia, the patient had abundant plasma cells in the BM and produced large quantities of IgM and IgG Abs, including autoantibodies. The proportion of naive B cells was reduced while the frequency of IgD–CD27– double-negative (DN) B cells, which quickly differentiated into Ab-secreting plasma cells upon stimulation, was greatly increased. Immune phenotype analysis of 52 patients with primary immunodeficiency revealed a strong association of the increased proportion of DN B and memory B cells with decreased number and proportion of naive B cells. These results suggest that the lymphopenic environment triggered naive B cell differentiation into DN B and memory B cells, leading to increased Ab production.
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